Letters in Drug Design & Discovery - Volume 4, Issue 6, 2007

In this paper we report the synthesis and the inhibition on Human Leucocyte Elastase (HLE) of a new series of thieno[2,3-d][1,3]oxazin- or thioxazin-4-ones 3a-o and thieno[3,2-d][1,3]oxazin- or thioxazin-4-ones 6a-d. New derivatives have inhibitory activity in the micromolar range and among them, 2-(3- trifluoromethylphenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one 3h and 5,6-dimethyl-2-(4-nitrophenylamino)- 4H-thieno[2,3-d][1,3]thioxazin-4-one 3o were the most interesting.

We report the results of our study into a series of 3,5-dibrominated derivatives of esters of 4- [(aminosulfonyl)oxy]benzoate as potential inhibitors of estrone sulfatase (ES). The results suggest that the compounds are weak inhibitors as a result of the incorporation of the bromine atoms which reduce the stability of the compound.

We report the results of the synthesis and biochemical evaluation of esters of 4-[(aminosulfonyl)oxy]benzoate as potential inhibitors of estrone sulfatase (ES). Modelling the compounds shows that steric interaction between the inhibitor and the active site is a major factor responsible for the weak inhibitory activity observed within the synthesised compounds.

Oxoquinolineribonucleosides 1a-j were prepared. These substances were screened for antiviral activity on HSV-1 virus infection, assessed by virus yield assay. The chlorosubstituted ribonucleosides 1b and 1g were the best inhibitors of HSV-1 yield with EC50 of 1.5 ± 0.06 μM and 1.7 ± 0.08 μM, respectively. Compound 1b presented the best selectivity index (SI) with an SI value of 1000.

A self-organizing map (SOM) was used for identification of synthetic tripeptides to HIV-1 TAR-RNA. This virtual screening strategy identified a phenanthrene-Arg-Arg sequence with an IC50 value of 5 μM. The SOM technique was shown to be applicable to RNA-ligand finding following an entirely ligand-based approach.

The structure activity relationship of omuralide-based 20S proteasome inhibitors is assessed via a COMBINE model incorporating covalent inhibitors. Reasonable correlation (R2 = 0.84) and predictivity (Q2 = 0.66) is obtained relative to experiment. The model confirms prior SAR assertions and suggests lead refinements involving polar substitution onto the lactacystin ring.

A molecular rational basis for the COX-2/COX-1 selectivity of lumiracoxib using molecular docking approach is described. The COX-2 docking analysis for lumiracoxib and the diclofenac analogue revealed a similar binding mode, in contrast with the COX-1 docking analysis which revealed a different binding orientation for both inhibitors.

A critical characteristic of optimized liposomal delivery systems is controlled drug release. This report describes the use of the monoacyl cationic lipids stearylamine (SA) and sphingosine (SPH), in conjunction with a transmembrane pH gradient, to enhance retention of the anticancer agent vincristine within liposomes administered intravenously to mice. The addition of SA to liposomes composed of distearoylphosphatidylcholine (DSPC) and cholesterol (Chol), to achieve a final composition of DSPC/Chol/SA at ratios of 45/45/10 (mol/mol/mol), caused a significant improvement in vincristine retention in the circulation of mice when combined with a transmembrane pH gradient of 5 units. Specifically, the presence of SA in liposomes having an internal pH (pHi) of 2.0 had a plasma vincristine AUC of 41.8 mg.h/100 mL plasma, compared to a vincristine AUC in the plasma of 28.0 mg.h/100 mL for identical liposomes lacking SA; an increase of 49%. Similar effects were observed with 10 mol% of the cationic lipid SPH. Comparison to control formulations lacking SA or SPH, or with smaller pH gradients (3 units), showed that improved vincristine retention required both the cationic lipid and the larger pH gradient. The presence of SA or SPH significantly improved vincristine pharmacokinetics due to the increased drug retention, but did not adversely alter the liposome pharmacokinetics. Enhanced retention of vincristine using SPH and a transmembrane pH gradient was associated with significant increases in anti-tumor activity against the murine P388 leukemia. The results are directly relevant to the use of charged lipid components to improve the drug retention/release attributes and the use of cationic lipids to promote accumulation at tumor-associated vascular endothelium.

Adenylyl cyclase is a membrane-bound enzyme that catalyzes the conversion of ATP to cAMP upon various hormonal stimulations. Isoform-selectivity among forskolin derivatives that forskolin and its derivatives are a direct activator of adenylyl cyclase, can be predicted mostly by the distribution of the negative electrostatic potential of each derivative.

Retinoic acid analogs containing an aromatic ring fixed between the 5 and 8 positions of retinoic acid, were synthesized by a palladium-catalyzed cross-coupling reaction between boronic acid and an alkenyltriflate or alkenyliodide. The biological activities of the retinoic acid analogs were evaluated.

Lamotrigine is thought to act at voltage-sensitive sodium channels to stabilize neuronal membranes and inhibit the release of excitatory amino acid neurotransmitters (e.g. glutamate, aspartate) that are thought to play a role in the generation and spread of epileptic seizures. In placebo-controlled clinical studies, lamotrigine has been shown to be effective in reducing seizure frequency and the number of days with seizures when added to existing antiepileptic drug therapy in adult patients with partial seizures, with or without generalized tonic-clonic seizures, that are not satisfactorily controlled. Lamotrigine has emerged as a first line treatment for bipolar depression, which is an area of weakness for other mood stabilizers, with positive effect for resistant bipolar disorders and rapid cycling bipolar disorders. We review the Literature on the topic with a specific interest on bipolar disorders.

Biocompatibility remains the central theme for biomaterials applications in medicine. It is generally accepted that this term does not indicate only absence of a cytotoxic effect but also positive effects in the sense of biofunctionality, i.e. promotion of biological processes considering the intended aim of the application of a biomaterial. Biocompatibility of zirconia gel glass was studied using in vitro testing methods, the incubation period was 7, 14, 21 days. The bioactivity of the synthesized material had been shown by the formation of a layer of hydroxyapatite on the surface of ZrO2-Y2O3(5wt%) samples soaked in a fluid simulating the composition of the human blood plasma (SBF), as observed by SEM and EDS microscopy. Studies of drug delivery kinetics were also carried out. The amount of sodium ampicillin released has been detected by UV-VIS spectroscopy. The released kinetics seems to occur in more than one stage. HPLC analysis had also been carried out to ensure the integrity of ampicillin after the synthetic treatment.